17(R),18(S)-Epoxyeicosatetraenoic Acid, a Potent Eicosapentaenoic Acid (EPA) Derived Regulator of Cardiomyocyte Contraction: Structure–Activity Relationships and Stable Analogues
journal contributionposted on 2011-06-23, 00:00 authored by John R. Falck, Gerd Wallukat, Narender Puli, Mohan Goli, Cosima Arnold, Anne Konkel, Michael Rothe, Robert Fischer, Dominik N. Müller, Wolf-Hagen Schunck
17(R),18(S)-Epoxyeicosatetraenoic acid [17(R),18(S)-EETeTr], a cytochrome P450 epoxygenase metabolite of eicosapentaenoic acid (EPA), exerts negative chronotropic effects and protects neonatal rat cardiomyocytes against Ca2+-overload with EC50 ≈ 1–2 nM. Structure–activity studies revealed that a cis-Δ11,12- or Δ14,15-olefin and a 17(R),18(S)-epoxide are minimal structural elements for antiarrhythmic activity whereas antagonist activity was often associated with the combination of a Δ14,15-olefin and a 17(S),18(R)-epoxide. Compared with natural material, the agonist and antagonist analogues are chemically and metabolically more robust and several show promise as templates for future development of clinical candidates.
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nMeicosapentaenoic acidStableEPAmaterialRelationshipfuture developmenttemplateolefinantagonist analoguesPotent EicosapentaenoicmetabolicallycombinationECcytochrome P 450 epoxygenase metabolitechronotropic effectscandidateDerived Regulatorantiarrhythmic activityantagonist activityrat cardiomyocytesshow promiseAnalogueCardiomyocyte Contraction